PROJECT SUMMARY Bronchopulmonary dysplasia (BPD) in preterm infants is a common and often severe lung disease with long term sequelae. Therapeutic options for the prevention and treatment of BPD are limited and have not substantially affected the incidence of disease, nor are there any early clinical biomarkers of disease. In clinical trials of inhaled nitric oxide (iNO), the incidence of BPD was reduced in a race-specific manner. Our goal is to understand the biological basis of BPD and response to therapies in preterm infants at high risk of disease. We hypothesize that the development of BPD is characterized by changes in the urinary metabolome throughout postnatal lung development, disease progression and therapies, and that these changes vary by race/ethnicity and genomic ancestry. We will test our hypothesis with two specific aims. Specific Aim 1: Characterize the urinary metabolome of preterm infants. We will detect and quantify urinary metabolites of 350 highly phenotyped preterm infants from two multi-center studies. We will compare metabolic profiles before and after starting iNO therapy, and with other treatments that influence metabolic state. We will identify changes in the urinary metabolome of infants with and without a diagnosis of BPD at 36 wk post menstrual age. Results from this aim will provide new information on the urinary metabolome of preterm infants, and we expect to identify metabolites and pathways associated with therapies and respiratory outcome that could provide novel biomarkers and insight into disease pathogenesis. Specific Aim 2: Examine the contribution of genomic ancestry to the urinary metabolome of preterm infants. We will investigate the contribution of race/ethnicity and genomic ancestry to metabolic profiles using existing genetic data for the same infants. We expect to identify metabolites that are associated with genomic ancestry independent of race/ethnicity, thus identifying those with a heightened genetic determination. Results from this aim will provide new information as to the role of genetic ancestry on the urinary metabolome of preterm infants, notably as it relates to racial/ethnic differences in BPD and response to iNO therapy. If this proposal is successful, it will transition into a larger proposal with the aim of querying the metabolome at additional time points throughout postnatal development, and directly integrating metabolomics with genetic associations studies of BPD and response to therapies. Relevance: Our major goals are to characterize and identify changes in the urinary metabolome of preterm infants with respect to bronchopulmonary dysplasia (BPD) and response to therapies. Results from this proposal will facilitate the development of biomarkers and precision targeted therapies, and advance our understanding of disease pathogenesis in a vulnerable pediatric population.